GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1) kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions. PK data from the first time in human (FTIH) study for GSK2982772 showed that the half life of GSK2982772 was short (approximately 2 to 3 hours). A once daily (QD) formulation would be more convenient from a subject perspective and could offer the advantage of providing a flatter GSK2982772 concentration time profile. Following completion of Parts A and B, it was determined that the slowest minitab formulation provided a PK profile suitable for QD dosing but this formulation was susceptible to a food effect. This study will evaluate the pharmacokinetics of GSK2982772 following administration of different minitab MR formulations in a capsule relative to an IR reference tablet formulation, the pharmacokinetics of selected MR formulation in capsule following repeat doses for 3 days and to compare the pharmacokinetics of GSK2982772 following administration of MR tablet formulations in the fed and fasted state relative to an IR tablet formulation. The study is divided into three parts: Part A will be a non-randomized 6 periods, sequential, 6-way fixed sequence design in which up to 4 MR minitab formulations in a capsule will be evaluated. Periods 1, 2, and 3 will evaluate a slow MR release duration (nominally 24 hours), a fast MR release duration (nominally 10 hours), and IR tablet respectively. Periods 4, 5 and 6 will have flexible dose regimen and it will depend on the outcomes of Period 1 to 3. Subjects will be admitted to the clinic the previous day before dosing. Each in-patient period will consist of 3 days and 2 nights followed by a minimum washout period of 7 days between doses, for both Part A and C. In Part A and C, 16 healthy subjects will be enrolled such that at least 12 evaluable subjects complete the study. Part B will be an open-label, repeat dose study in which the selected MR minitab formulation in capsule will be evaluated. Each in-patient period will consist of 5 days and 4 nights. There will be a minimum of 7 days washout period between the last morning dose of one period and the first dose of the next period. In Part B, 10 healthy subjects will be enrolled such that at least 6 evaluable subjects complete the study. Part C of the study will be a non-randomised 6 period, sequential, fixed sequence crossover design in which MR tablet formulations will be evaluated. Periods 1 and 2 will evaluate single dose administration of a 240 milligram (mg) MR tablet and the 240 mg IR tablet (reference), respectively. Periods 3, 4, 5 and 6 will be flexible and the dosing regimen will be dependent on the outcome of Periods 1 and 2.
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Area Under the Curve From Time Zero to Infinity (AUC[0-inf]) of GSK2982772 in IR Formulation: Part A
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose
AUC(0-inf) of GSK2982772 in MT Formulation :Part A
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose
Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC[0-t]) of GSK2982772 in IR Formulation : Part A
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose
AUC(0-t) of GSK2982772 in MT Formulation: Part A
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose
Area Under the Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK2982772 in IR Formulation: Part A
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose
AUC(0-24) of GSK2982772 in MT Formulation: Part A
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose
Area Under the Curve From Time Zero to 12 Hours (AUC[0-12]) of GSK2982772 in IR Formulation: Part A
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours post-dose
AUC(0-12) of GSK2982772 in MT Formulation: Part A
Timeframe: Pre-dose, 2, 4, 6, 8, 10, and 12 hours post-dose
Maximum Observed Concentration (Cmax) of GSK2982772 in IR Formulation: Part A
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose
Cmax of GSK2982772 in MT Formulation: Part A
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose
Concentration at 12 Hours Post-dose (C12hour) of GSK2982772 in Part A
Timeframe: 12 hours post-dose
Concentration at 24 Hours Post-dose (C24hour) of GSK2982772 in Part A
Timeframe: 24 hours post-dose
Relative Bioavailability (Frelformulation) Based on AUC (0-inf) of GSK2982772 in Part A
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose (reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose (test)
Frelformulation Based on AUC (0-24) of GSK2982772 in Part A
Timeframe: Pre-dose 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose (reference); Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose (test)
Frelformulation Based on Cmax of GSK2982772 in Part A
Timeframe: Pre-dose,0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose(reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose(test)
Ratio of Cmax to C12hour of GSK2982772 in IR Formulation: Part A
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 26, 28, 30 and 32 hours post-dose
Ratio of Cmax to C12hour of GSK2982772 in MT Formulation: Part A
Timeframe: Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose
Ratio of Cmax to C24hour of GSK2982772 in IR Formulation: Part A
Timeframe: Pre-dose 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose
Ratio of Cmax to C24hour of GSK2982772 in MT Formulation: Part A
Timeframe: Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose
Time to Cmax (Tmax) of GSK2982772 in IR Formulation: Part A
Timeframe: Pre-dose 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose
Tmax of GSK2982772 in MT Formulation: Part A
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose
AUC(0-inf) of GSK2982772 for IR Formulation in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
AUC(0-inf) of GSK2982772 for MM Formulation in Part C: Fasted State
Timeframe: Pre-dose, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose
AUC(0-t) of GSK2982772 for IR Formulation in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
AUC(0-t) of GSK2982772 for MM Formulation in Part C: Fasted State
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose
AUC(0-24) of GSK2982772 for IR Formulation in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
AUC(0-24) of GSK2982772 for MM Formulation in Part C: Fasted State
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours post-dose
AUC (0-12) of GSK2982772 for IR Formulation in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose
AUC (0-12) of GSK2982772 for MM Formulation in Part C: Fasted State
Timeframe: Pre-dose, 2, 4, 6, 8, 10, and 12 hours post-dose
Cmax of GSK2982772 for IR Formulation in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Cmax of GSK2982772 for MM Formulation in Part C: Fasted State
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose
C12 of GSK2982772 in Part C: Fasted State
Timeframe: 12 hours post-dose
C24 of GSK2982772 in Part C: Fasted State
Timeframe: 24 hours post-dose
Ratio of Cmax to C12hour of GSK2982772 for IR Formulation in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Ratio of Cmax to C12hour of GSK2982772 for MM Formulation in Part C: Fasted State
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose
Ratio of Cmax to C24hour of GSK2982772 for IR Formulation in Part C: Fasted State
Timeframe: Pre-dose,0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Ratio of Cmax to C24hour of GSK2982772 for MM Formulation in Part C: Fasted State
Timeframe: Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose
Frelformulation Based on AUC (0-t) of GSK2982772 in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose(reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose(test)
Frelformulation Based on AUC (0-24) of GSK2982772 in Part C: Fasted State
Timeframe: Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose(reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours post-dose(test)